Pyridine-containing Macrocycle Research Articles

Molecular Necklaces Formed Through Zn2+-Templated Binding of Macrocycles with Dynamically Formed Imines as Guest Recognition Sites.

Herein we demonstrate an "in-ring establishing" strategy for assembling interlocked molecules through dynamic imine formation, "establishing" the host recognition sites in situ. Using Zn2+ ions to template the assembly of a pyridine-containing macrocycle with semidumbbell-shaped triazole-containing aldehyde and amine derivatives, we obtained the corresponding [2]rotaxane in high yield (85 %) after subsequent imine reduction (NaBH4) and amine protonation (NH4PF6). We performed the same three steps (assembly, reduction, protonation) to prepare a stable and highly symmetrical [5]molecular necklace ([5]MN) from 12 components (two almost-90°-oriented dialdehydes, two almost-90°-oriented diamines, four macrocycles, four Zn2+ ions) in an overall yield of 69 %.

Pyridine-Containing Macrocycles Display MMP-2/9 Inhibitory Activity and Distinct Effects on Migration and Invasion of 2D and 3D Breast Cancer Models.

The role of metalloproteinases (MMPs) on the migration and invasion of cancer cells has been correlated with tumor aggressiveness, namely with the up-regulation of MMP-2 and 9. Herein, two pyridine-containing macrocyclic compounds, [15]pyN5 and [16]pyN5, were synthesized, chemically characterized and evaluated as potential MMP inhibitors for breast cancer therapy using 3D and 2D cellular models. [15]pyN5 and [16]pyN5 (5–20 µM) showed a marked inhibition of MMPs activity (100% at concentrations ≥ 7.5 μM) when compared to ARP-100, a known MMP inhibitor. The inhibitory activity of [15]pyN5 and [16]pyN5 was further supported through in silico docking studies using Goldscore and ChemPLP scoring functions. Moreover, although no significant differences were observed in the invasion studies in the presence of all MMPs inhibitors, cell migration was significantly inhibited by both pyridine-containing macrocycles at concentrations above 5 μM in 2D cells (p < 0.05). In spheroids, the same effect was observed, but only with [16]pyN5 at 20 μM and ARP-100 at 40 μM. Overall, [15]pyN5 and [16]pyN5 led to impaired breast cancer cell migration and revealed to be potential inhibitors of MMPs 2 and 9.

Synthesis and crystal structure of [2,7,12-trimethyl-3,7,11,17-tetra-aza-bicyclo-[11.3.1]hepta-deca-1(17),13,15-triene-κ(4) N]copper(II) bis-(perchlorate).

The title copper(II) complex of a pyridine-containing macrocycle (PyMAC), [Cu(C16H28N4)](ClO4)2, has been prepared. The crystal structure reveals the Cu(II) atom to be octahedrally coordinated by a tetradentate aminopyridine macrocyclic ligand surrounding the metal cation in a square-planar geometry. Two weakly bound perchlorate counter-ions occupy the axial sites above and below the macrocyclic plane. The crystal studied was refined as a two-component pseudo-merohedral twin; the refined fractional contribution of the minor component is 38.77 (8).

Unexpected One-Step Formation of Iodo[1,3]dioxolo[4,5-c]pyridine Derivatives by a Hofmann-Löffler-Freytag Reaction: Studies on the Synthesis of a Pyridine-Containing Macrocycle

During attempts to prepare functionalized 5-iodopyridine derivatives the unexpected formation of iodo[1,3]dioxolo[4,5-c]pyridines was discovered. The conversion of 3-alkoxypyridin-4-ols into the corresponding 5-iodo compounds was achieved by reaction with one equivalent of iodine or tetramethylammonium dichloroiodate under basic conditions. When three equivalents of iodine were used in chlorinated solvents, after 5-iodination, subsequent reaction of the 3-alkoxy group took place to form a 1,3-dioxolane ring with the 4-hydroxyl group. Generation of the resulting iodo[1,3]dioxolo[4,5-c]pyridines is explained by a radical process known as the Hofmann–Loffler–Freytag reaction. Two 6-ethynylpyridine derivatives were examined in the iodination process to establish a route to pyridine-containing macrocycles. The pentasubstituted 5-iodopyridine derivative 21 could be prepared; however, attempts to achieve cyclotrimerization of this building block under different conditions were not successful. Reaction of 21 with copper chloride allowed isolation of a copper acetylide 22, which aggregates to a triangular trimeric complex containing four copper(I) ions such as [23·Cu]+ as monitored by ESI mass spectrometry.

Oxygen atom transfer mediated by an iron(IV)/iron(II) macrocyclic complex containing pyridine and tertiary amine donors

A new non-heme iron model complex containing a high-spin iron(II) complexed with N-methylated pyridine-containing macrocycle was synthesized and crystallographically characterized. The complex generates peroxo- and high-valent iron-oxo intermediates in reactions with tert-butylhydroperoxide and isopropyl 2-iodoxybenzoate, respectively, allowing to gain insight into the formation and reactivity of enzyme-like intermediates related to biological oxygen activation. The formation and reactivity of these intermediate species were investigated by the stopped-flow methodology. The mechanism of oxygen transfer to organic substrates involving reaction of oxoiron(IV) intermediate was elucidated on the basis of spectroscopic and kinetic data. Incorporation of a pyridine ring into the macrocycle increased the reactivity of the FeIVO intermediates in comparison with polyamine tetraaza macrocyclic complexes: ferryl (FeIVO) species derived from 3 demonstrated electrophilic reactivity in transferring an oxygen atom to substituted triarylphosphines and to olefins (such as cyclooctene). However, iron(III) alkylperoxo intermediate was unreactive with cyclooctene.

Synthesis and structure of expanded pyriporphyrins containing a dipyrrylpyridine unit

Expanded pyriporphyrins with five and ten nitrogens were prepared in 67% and 6.5% yield, respectively, by the reactions of bis(azafulvene) and dipyrrylpyridine. The minimum 17-membered non-aromatic macrocycle made of four pyrroles and one pyridine is highly non-planar in comparison with orangarin that contains a tripyrrole unit instead of a dipyrrylpyridine unit. This highly non-planar ring structure is basically unchanged in the complex with trifluoroacetic acid (TFA) where carboxylate anions are bound on both sides of the macrocyle plane by multiple hydrogen bondings. This monopyridine-tetrapyrrole hybrid macrocycle was able to act as a dianionic ligand for various metal ions including lanthanide ions. In contrast to the reported figure eight type X-ray structure of turcasarin that is a double sized macrocycle of orangarin, the pyridine-containing macrocycle analog of the same 34-membered ring size isolated in this study was found not to take a figure eight type conformation as evidenced by X-ray crystallography of the tetracation with TFA anions.

Influence of Charge on Anion Receptivity in Amide-Based Macrocycles

Binding and structural aspects of anions with tetraamido/diquaternized diamino macrocyclic receptors containing m-xylyl, pyridine, and thiophene spacers are reported. (1)H NMR studies indicate that the quaternized receptors display higher affinities for anions compared to corresponding neutral macrocycles. The macrocycles containing pyridine spacers consistently display higher affinity for a given anion compared to those with either m-xylyl or thiophene spacers. The m-xylyl- and pyridine-containing receptors exhibit high selectivity for H(2)PO(4)(-) in DMSO-d(6) with association constants, K(a) = 1.09 × 10(4) and >10(5) M(-1), respectively, and moderate selectivity for Cl(-) with K(a) = 1.70 × 10(3) and 5.62 × 10(4) M(-1), respectively. Crystallographic studies for the Cl(-) and HSO(4)(-) complexes indicate that the m-xylyl-containing ligand is relatively elliptical in shape, with the two charges at ends of the major axis of the ellipse. The anions are hydrogen bonded with the macrocycle but are outside the ligand cavity. In the solid state, an unusual low-barrier hydrogen bond (LBHB) was discovered between two of the macrocycle's carbonyl oxygen atoms in the HSO(4)(-) complex. The pyridine-containing macrocycle folds so that the two pyridine units are face-to-face. The two I(-) ions are chelated to the two amides adjacent to a given pyridine. In the structure of the thiophene containing macrocycle with two BPh(4)(-) counterions, virtually no interaction was observed crystallographically between the macrocycle and the bulky anions.

Catalytic “Active-Metal” Template Synthesis of [2]Rotaxanes, [3]Rotaxanes, and Molecular Shuttles, and Some Observations on the Mechanism of the Cu(I)-Catalyzed Azide−Alkyne 1,3-Cycloaddition

A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.

Pyridine‐Containing Macrocycles via Cobalt‐Mediated [2 + 2 + 2] Cycloadditions of α,ω‐Bisalkynes

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Synthesis and Catalytic Properties in Olefin Epoxidation of Novel Iron(II) Complexes with Pyridine-Containing Macrocycles Bearing an Aminopropyl Pendant Arm

Three novel iron(II) complexes with pyridine-containing macrocycles bearing an aminopropyl pendant arm were synthesized and characterized. Crystal structures of two of the complexes revealed high-spin iron(II) centers coordinated to the five ligand nitrogen atoms with no coordination of either the solvent molecules or anions, resulting in an unusual square-pyramidal geometry. Related tetradentate ligand CRH formed a low-spin iron(II) complex (meso form was structurally characterized) with a planar arrangement of the four nitrogen atoms from the macrocycle and two axial acetonitrile molecules. Similarly to the corresponding nickel and copper complexes of the pentadentate ligands, the protonation of the amino group on the ligand arm in iron(II) complexes was found to be reversible. Spectral changes and magnetic susceptibility measurements indicated that a change in the geometry and spin state of the metal center is associated with this acid-base process. In the presence of noncoordinating acids (e.g., triflic acid), these complexes, as well as their nonmethylated analogue, can efficiently catalyze the epoxidation of cyclooctene and 1-decene under mild conditions, using hydrogen peroxide as the oxidant. However, in the deprotonated form or in the presence of coordinating acids like HCl, no epoxidation occurs.

Pyridine-containing macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions of α,ω-bis-alkynes

We have been investigating the formation of macrocycles from α,ω-diynes in Co(I)-mediated cocyclotrimerization reactions. In these metal-mediated [2 + 2 + 2] cycloadditions, long-chain α,ωdiynes were reacted with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, in the form of meta- and parapyridinophanes (e.g., 5m/5p, 35m/35p, 41m/41p). The regioselectivity of these reactions was influenced by the length and type of linker unit between the alkyne groups, as well as by stereoelectronic factors. We developed an improved reaction protocol for these Co(I)-promoted [2 + 2 + 2] cycloadditions that offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield, at ca. 100 °C in 24 h, without photo-irradiation or syringe-pump addition. With this improved protocol, we were able to co-cyclotrimerize longchain α,ω-diynes with alkynes in certain cases to effect a macrocyclic variant of the Vollhardt reaction (e.g., 6 + Pr-C≡C-Pr → 56p). We used our improved [2 + 2 + 2] cycloaddition method to synthesize some macrocyclic bis-indolemaleimides as potential protein kinase inhibitors. Thus, we prepared “multiheterophanes” 63p, 63m, and 64p and determined that they are potent, selective inhibitors of glycogen synthase kinase-3β (GSK-3β).

Equilibrium and Formation/Dissociation Kinetics of Some LnIIIPCTA Complexes

The protonation constants () of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) and stability constants of complexes formed between this pyridine-containing macrocycle and several different metal ions have been determined in 1.0 M KCl at 25 degrees C and compared to previous literature values. The first protonation constant was found to be 0.5-0.6 log units higher than the value reported previously, and a total of five protonation steps were detected (log = 11.36, 7.35, 3.83, 2.12, and 1.29). The stability constants of complexes formed between PCTA and Mg2+, Ca2+, Cu2+, and Zn2+ were also somewhat higher than those previously reported, but this difference could be largely attributed to the higher first protonation constant of the ligand. Stability constants of complexes formed between PCTA and the Ln3+ series of ions and Y3+ were determined by using an "out-of-cell" potentiometric method. These values ranged from log K = 18.15 for Ce(PCTA) to log K = 20.63 for Yb(PCTA), increasing along the Ln series in proportion to decreasing Ln3+ cation size. The rates of complex formation for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA) were followed by conventional UV-vis spectroscopy in the pH range 3.5-4.4. First-order rate constants (saturation kinetics) obtained for different ligand-to-metal ion ratios were consistent with the rapid formation of a diprotonated intermediate, Ln(H(2)PCTA)(2+). The stabilities of the intermediates as determined from the kinetic data were 2.81, 3.12, 2.97, and 2.69 log K units for Ce(H(2)PCTA), Eu(H(2)PCTA), Y(H(2)PCTA), and Yb(H(2)PCTA), respectively. Rearrangement of these intermediates to the fully chelated complexes was the rate-determining step, and the rate constant (k(r)) for this process was found to be inversely proportional to the proton concentration. The formation rates (k(OH)) increased with a decrease in the lanthanide ion size [9.68 x 10(7), 1.74 x 10(8), 1.13 x 10(8), and 1.11 x 10(9) M(-1) s(-1) for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA), respectively]. These data indicate that the Ln(PCTA) complexes exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid-catalyzed dissociation rates (k1) varied with the cation from 9.61 x 10(-4), 5.08 x 10(-4), 1.07 x 10(-3), and 2.80 x 10(-4) M(-1) s(-1) for Ce(PCTA), Eu(PCTA), Y(PCTA), and Yb(PCTA), respectively.

Porphyrinic assemblies of pyridine-containing macrocycles

Using a combination of palladium-catalyzed cross-coupling and copper-catalyzed homocoupling reactions, two pyridine-containing macrocycles with varying pendant substitution were constructed. Their synthesis and subsequent coordination to a ruthenium porphyrin is described. In addition to synthetic details and characterization, an examination of their electronic properties is provided.

Synthesis of Macrocycles via Cobalt‐Mediated [2 + 2 + 2] Cycloadditions

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Macrocycles via Cobalt-Mediated [2 + 2 + 2] Cycloadditions

We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.

Reactions of py[13]aneN4 with the copper(II) complexes of diglycine and triglycine

Ligand exchange reactions between the pyridine-containing macrocycle 3,7,10,16-tetraazabicyclo[10,3,1]-hexadeca-1,(16),12,14,-triene, py[13]aneN4, and the Cu(II) complexes of diglycine (GG) and triglycine (GGG) have been investigated in aqueous solution. The kinetics were studied by stopped-flow techniques at 25°C and I = 0.2 M (KNO3). A single kinetic step was observed at the d–d transition band (λ max = 580 nm) for the Cu(II) macrocycle. All kinetic measurements were carried out under pseudo first-order conditions in the pH range 5.0–6.2 with the ligand concentration at least 10-fold excess. The specific rate constant, k i , for the two systems studied describes the reaction between the 1 : 1 Cu(II)-polyglycine complex and the monoprotonated form, LH+, of the macrocycle. Cu(II)-GGG complexes exchange the metal more rapidly than the corresponding Cu(II)-GG complexes: where k 1 = 9.1 × 105 and 5.8 × 106 M−1 s−1 and k 2 = 2.5 × 105 and 1.3 × 106 M−1 s−1 for the GG and GGG systems, respectively. The reaction mechanisms of these reactions are discussed. Formation constants for the ternary systems Cu-GG-py[13]aneN4 and Cu-GGG-py[13]aneN4 are evaluated by pH-electrode titrations in aqueous solution at 25°C and I = 0.2 M (KNO3). Attempts to separate the solid ternary compounds from the blue perchlorate solution mixture of Cu(II), py[13]aneN4 and GG (or GGG) were unsuccessful. Instead, red plate-shaped crystals separated from the blue solution. The crystal structure of the red compound [Cu(py[13]aneN4)](ClO4)2 was determined. E-mail: marohayat@hotmail.com

Mannich reaction as a new route to pyridine-based polyaminocarboxylic ligands.

The Mannich reaction was successfully employed to obtain two pyridine-based ligands 1 and 2. The latter represents the first example of a Mannich reaction leading to a 12-membered pyridine-containing macrocycle. [reaction: see text]

A new family of NxOy pyridine-containing macrocycles: Synthesis and characterization of their Y(III), Ln(III), Zn(II), and Cd(II) coordination compounds

Reaction between 2,6-bis(2-formylphenoxymethyl)pyridine and N,N-bis(3-aminopropyl)methylamine or tris(2-aminoethyl)amine has been used as the starting point for the synthesis of seven oxa-aza macrocyclic ligands, five of them never reported previously. They all feature different pendant arms, which provide a wide range of coordination possibilities. The Schiff base macrocycles L1 and L4 and their reduced ligands L2 and L5 are derived from 2,6-bis(2-formylphenoxymethyl)pyridine and tris(2-aminoethyl)amine or N,N-bis(3-aminopropyl)methylamine, respectively. The reaction of L1 with salicylaldehyde forms L3, which features an imine bond in the pendant arm. The ligand L5 has been the precursor for the pendant-armed L6 and L7, by alkylation of the free NH groups with methyl-imidazole or methyl-indole. By a template or a nontemplate approach, we have synthesized different mono- and dinuclear complexes with Y(III), Ln(III), Zn(II), and Cd(II) cations. Both the free macrocyclic ligands and their corresponding metal complexes have been characterized by microanalysis, IR, UV–vis, 1H and 13C NMR spectroscopy, FAB mass spectrometry, MS electrospray, and conductivity measurements.Key words: Schiff-base macrocycle, template synthesis, macrocyclic ligand complexes, lanthanide(III) complexes.

Using ligand exchange reactions to control the coordination environment of Pt(II) acetylide complexes: applications to conjugated metallacyclynes

Ligand exchange of cis-bis(diphenylphosphino)ethylene (dppee) with trans-(Ph 3P) 2Pt(CCR) 2 easily generates the cis-complexes (dppee)Pt(CCR) 2 in 64–95% yield. This transformation is used to convert pyridine-containing macrocycle 7 to its cis-analogue 8 and the macrocyclic bipyridine analogue 10 to the unique macrocyclic ligand 11. X-ray structural characterization of trans-complexes 5a and 5b and cis-complexes 6a and 6b are reported, as is the structure of the strained macrocycle 8.

Synthesis of Pyridine-Containing Macrocycles by Cobalt-Mediated Trimerization of Triply-Bonded Species [J. Am. Chem. Soc. 2001, 123, 3157−3158

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionSynthesis of Pyridine-Containing Macrocycles by Cobalt-Mediated Trimerization of Triply-Bonded Species [J. Am. Chem. Soc.2001, 123, 3157−3158].Alessandro F. Moretto, Han-Cheng Zhang, and Bruce E. MaryanoffCite this: J. Am. Chem. Soc. 2002, 124, 23, 6792Publication Date (Web):May 15, 2002Publication History Published online15 May 2002Published inissue 1 June 2002https://doi.org/10.1021/ja025102zCopyright © 2002 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views444Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (15 KB) Get e-Alerts Get e-Alerts